Memory Studies with Adrenoceptor Agonists and Antagonists in Chicks

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We have systematically investigated the roles of adrenoceptors in the action of noradrena-line in a one trial learning task (discriminated avoidance learning) in the young chick, where the chick discriminates between red and blue beads. The chick at one to two days of age has a number of distinct advantages over rodents in the study of memory, including limited development of the blood brain barrier, the ability to learn about coloured beads in one short trial without any prior knowledge of colored beads. When chicks are readily available from nearby poultry farms (as male rejects from an egg laying strain), they are inexpensive, available in sufficient numbers for large experiments from the same hatch and available soon after sex determination. As they are precocial, they can be used for experiments on the day of arrival and do not need to be housed for more than one day. Birds have a visual system with similar capabilities to humans and are active during the day unlike rodents. The structure of the avian brain, once thought to be very dissimilar to that of mammals, is now considered to have the same components (although perhaps packaged in a different way). For example, there is a close similarity between rats and pigeons in hippocampal functions with respect to spatial memory.13 The primary visual, somatosensory and motor cortices are also similarly structured.48

The one trial peck avoidance task that is used with young chicks in various versions (passive avoidance, or discriminated avoidance) has changed subtly over the years since first introduced by Cherkin and Lee-Teng11 and Watts and Mark.74 But the task is still essentially the suppression of pecking at a bead that has the bitter taste of methyl anthranilate. The chick pecks at the bead on the training trial and if it remembers the bitter taste it does not peck at beads of that colour on the retention trial. We now get the chicks to discriminate between a clean red bead (this color was associated with methyl anthranilate on the training trial) and a blue bead and measure memory retention by the ratio of pecks to red and blue on the two successive 10 second retention trials. This gives a memory score for each chick, called the discrimination ratio (DR). If a chick remembers, it pecks less on the red bead and has a DR approaching 1.0 (Fig. 5B); if it forgets, the chick pecks at both beads equally and the DR approaches 0.5. Chicks are trained in groups of up to 20 and memory is measured in separate groups of chicks at prescribed times after training.

The memory time course which results from training with concentrated anthranilate on the bead reveals a model of memory where three stages are delineated by two periods (15 and 55 minutes after training) where the chicks appear to forget (Fig. 4). These two times correspond to the times for short-term, intermediate and long-term memory that have been defined on the basis of susceptibility to different classes of pharmacological drugs.26,30 These drugs inhibit memory when injected at particular times up to 30 minutes after training and inhibitors for each memory stage have characteristic time windows during which they have to be injected in order to inhibit memory.26,30 The determination of these times is also important for establishment of the roles of adrenoceptor subtypes in memory (see below, Table 3).

One particular advantage of this task is that the level of reinforcement, ie the concentration of the aversant on the bead, can be altered such that the retention level can be changed from good memory, with a level of 1.0 to poor memory with a retention level of 0.5. With weakly reinforced learning, memory lasts for 30 minutes and then the memory is lost (Fig. 5A). Memory is in a labile form and is not normally kept for longer than 30 minutes unless some event occurs which triggers the consolidation of the labile memory to a permanent form. This can be achieved

Figure 4. Sequences of memory stages in memory formation in the chick. This model is derived from behavioural and pharmacological experiments where memory is tested in separate groups of chicks at discrete times after training. Memory is measured as the discrimination between red and blue beads, where only the red bead had the aversive taste on training. A discrimination ratio approaching 1.0 is found where chicks avoid the red bead but peck the blue bead; a discrimination ratio approaching 0.5 is found when the chicks forget and peck at both beads equally. Behavioural experiments reveal two times after training when the chicks do not appear to remember. These time points coincide with data from pharmacological experiments, where memory decays after each of the stages following inhibition leaving the previous stage intact (from refs. 26,30). Theoretically, this represents the memory course within any one chick. At 30 minutes some internal event triggers the consolidation of labile memory into permanent storage. This time divides intermediate memory into phase A and phase B, each susceptible to interference by different pharmacological agents. Reprinted from Progress in Neurobiology, 67, 2002, pp. 345-391, Gibbs et al: "Role of adrenoreceptor subtypes in memory consolidation. Figure 1.

Figure 4. Sequences of memory stages in memory formation in the chick. This model is derived from behavioural and pharmacological experiments where memory is tested in separate groups of chicks at discrete times after training. Memory is measured as the discrimination between red and blue beads, where only the red bead had the aversive taste on training. A discrimination ratio approaching 1.0 is found where chicks avoid the red bead but peck the blue bead; a discrimination ratio approaching 0.5 is found when the chicks forget and peck at both beads equally. Behavioural experiments reveal two times after training when the chicks do not appear to remember. These time points coincide with data from pharmacological experiments, where memory decays after each of the stages following inhibition leaving the previous stage intact (from refs. 26,30). Theoretically, this represents the memory course within any one chick. At 30 minutes some internal event triggers the consolidation of labile memory into permanent storage. This time divides intermediate memory into phase A and phase B, each susceptible to interference by different pharmacological agents. Reprinted from Progress in Neurobiology, 67, 2002, pp. 345-391, Gibbs et al: "Role of adrenoreceptor subtypes in memory consolidation. Figure 1.

Figure 5. Data from experiments in which the chicks given (A) weakly reinforced training (20% anthra-nilate) or (B) strongly reinforced training (100% anthranilate). Separate groups of 20 chicks are tested at different times after training. With weakly reinforced training, memory gets weaker in chicks tested after 30-35 minutes; whereas with strongly reinforced training the level of memory retention is still high on the test 120min after training. This memory remains permanently good (at least 72 hours). Reprinted from Progress in Neurobiology, 67, 2002, pp. 345-301. Gibbs et al: Role of adrenoreceptor subtypes in memory consolidation. Figure 2.

Figure 5. Data from experiments in which the chicks given (A) weakly reinforced training (20% anthra-nilate) or (B) strongly reinforced training (100% anthranilate). Separate groups of 20 chicks are tested at different times after training. With weakly reinforced training, memory gets weaker in chicks tested after 30-35 minutes; whereas with strongly reinforced training the level of memory retention is still high on the test 120min after training. This memory remains permanently good (at least 72 hours). Reprinted from Progress in Neurobiology, 67, 2002, pp. 345-301. Gibbs et al: Role of adrenoreceptor subtypes in memory consolidation. Figure 2.

Table 3. Adrenoceptor agonists and antagonists used in chick discriminated avoidance learning

Subtype

Agonist

Antagonist

Route

Effect

a1 -AR

Methoxamine

IMHV

inhibit

Prazosin

enhance

a2-AR

Clonidine

LPO/IMHV

enhance

oxymetazoline

LPO

enhance

yohimbine*

LPO

Inhibit/

enhance

Yohimbine*

subcut

Inhibit/

enhance

ß1 -AR

RO363

LPO

enhance

isoprenaline

enhance

CGP 20712

LPO/sc

inhibit

propranolol

LPO/sc

inhibit

sotalol

inhibit

ß2-AR

isoprenaline

IMHV

enhance

zinterol

IMHV

Enhance

clenbuterol

Enhance

salbutamol

Enhance

BRL37344+

IMHV

enhance

Propranolol

IMHV

inhibit

Sotalol

inhibit

ICI 118,551

enhance

timolol

ß3-AR

isoprenaline

IMHV

enhance

CL316243

IMHV/sc

enhance

BRL37344

IMHV

enhance

CGP12177A

IMHV

enhance

SR59230A

IMHV/sc

inhibit

*It is clear that yohimbine can enhance the time administered after training. + High doses.

or inhibit depending

on route of adm

inistration and also on

by injection of noradrenaline or by hormonal or environmental events that may lead to increased endogenous release of noradrenaline. Memory improvement from enhancement of consolidation can be achieved by injection of drugs up to 30 min after training but not later.

Noradrenaline enhances memory of weakly reinforced training (20% anthranilate) when injected subcutaneously25,30 or when injected into two different brain regions - the intermediate medial hyperstriatum ventrale (IMHV-a multimodal sensory association area - association cortex) and the lobus parolfactorius (LPO- caudate putamen). The dose response relationship at 2 hours after training for intracerebral administration 20 minutes after training is a bell-shaped function, with low doses enhancing and higher doses inhibiting memory. Similar responses are seen in rats with systemic injection of adrenaline31 or clenbuterol34 or noradrenaline infused into the amygdala.43 By pre-administration of selective a- and P-AR antagonists (see Table 2; Fig. 6) we showed that the action of noradrenaline, injected into the IMHV, involves P2-, P3-, and a1-ARs, which are activated at different doses. Low doses of noradrenaline facilitate memory acting via P3-ARs; higher doses also facilitate memory by acting on P2-

Figure6. A) Dose response relationship for noradrenaline injected into IMHV 20 minutes after weakly reinforced training. Enhancement of memory consolidation by noradrenaline at doses of 0.1nmoles/hemi-sphere is attributed to action at |3-ARs; whereas at 1.0nmole/hemisphere noradrenaline is acting via |2-ARs. Higher doses of noradrenaline (3-10nmoles/hemisphere) do not enhance weakly reinforced memory and are inhibitory when used with 100% anthranilate. This inhibitory effect is attributed to an action on ai-ARS. B) Dose response relationship for noradrenaline injected into LPO at 20 minutes after weakly reinforced training. A similar bell-shaped relationship is seen, with the memory enhancing property attributed to |2-ARs.

Figure6. A) Dose response relationship for noradrenaline injected into IMHV 20 minutes after weakly reinforced training. Enhancement of memory consolidation by noradrenaline at doses of 0.1nmoles/hemi-sphere is attributed to action at |3-ARs; whereas at 1.0nmole/hemisphere noradrenaline is acting via |2-ARs. Higher doses of noradrenaline (3-10nmoles/hemisphere) do not enhance weakly reinforced memory and are inhibitory when used with 100% anthranilate. This inhibitory effect is attributed to an action on ai-ARS. B) Dose response relationship for noradrenaline injected into LPO at 20 minutes after weakly reinforced training. A similar bell-shaped relationship is seen, with the memory enhancing property attributed to |2-ARs.

ARs; and the highest doses of noradrenaline inhibit memory via a1-ARs. Pre-administration of the a2-AR antagonist yohimbine did not affect the response to noradrenaline injected into the IMHV, but did prevent the memory facilitation produced by noradrenaline injected into the LPO. In these experiments, noradrenaline was injected 20 minutes after training, during intermediate memory and prior to the consolidation into long-term memory. Although neither the |1-AR agonist RO363 nor the selective |1-AR antagonist CGP20712 influenced memory when given 20 minutes after training, we have evidence that |1-ARs in the LPO are involved in short-term memory.

Roles for Adrenoceptor Subtypes in the IMHV ai-Adrenoceptors

High doses of noradrenaline (10nmol/hemisphere) injected into the IMHV inhibit memory formation in chicks trained with 100% anthranilate, however, high doses of the |-AR agonist isoprenaline do not inhibit.27 The effect of high doses of noradrenaline is mimicked by injection of the selective a1-AR agonist methoxamine.29 Both noradrenaline and methoxamine injected into the IMHV prevent the consolidation of intermediate memory. There are two times of susceptibility to interference by stimulation of a1-ARs (Fig. 7). Injections made 5 minutes before training or 20 to 25 minutes after training affect memory, but injections at the times in between have no effect. At either time after training, memory was unaffected for 30 minutes, but then rapidly decays (Fig. 8A). Memory does not consolidate.

The specificity of the action of methoxamine on a1-ARs was demonstrated by pre-administration of the selective a1-AR antagonist prazosin. Given 5 minutes before methoxamine, prazosin shifted the dose-response curve in parallel to the right, ie. prazosin decreased the ability of methoxamine to inhibit memory.

fi2-Adrenoceptors

The non-selective |-AR agonist isoprenaline enhances memory consolidation in a similar manner to the lower dose range of noradrenaline (0.1 and 3.0 nmol/hemisphere). The action of isoprenaline (1 to 10 nmol) is prevented by pre- administration of the |1-/|2-AR antagonist

Memory Formation Repetition Stages
Figure 7. Schematic representation showing times and memory stages at which antagonists to the different subtypes are effective in preventing memory formation.
Hiv Subtypes Window Periods

Figure 8. Time of memory decay after injection of different AR subtype antagonists (with 100% anthra-nilate). A) aj, a2 and I2- AR antagonists do not impair labile memory but memory decays after 30 minutes and there is no consolidation. B) Memory decay after 10 minutes following the I3-AR antagonist, and from 10 minutes (or earlier) when propranolol's action is attributable to |j-ARs in the LPO.

Figure 8. Time of memory decay after injection of different AR subtype antagonists (with 100% anthra-nilate). A) aj, a2 and I2- AR antagonists do not impair labile memory but memory decays after 30 minutes and there is no consolidation. B) Memory decay after 10 minutes following the I3-AR antagonist, and from 10 minutes (or earlier) when propranolol's action is attributable to |j-ARs in the LPO.

propranolol.27 Although propranolol blocks both and p2-ARs, we were not able to demonstrate any effect of |j-AR agonists or antagonists given 20 minutes after training, suggesting that the action of propranolol on the enhancement of memory by isoprenaline 20 min after training is due to an action at |2-ARs.

Systemic injection after training of propranolol,15 sotalol67,68 and the selective P2-AR antagonist ICI11855118 have all been shown to inhibit memory, whereas the |1-AR antagonist atenolol does not. The selective P2-AR agonist, salbutamol enhanced weakly reinforced training and facilitated retention in chicks treated with the noradrenergic neurotoxin DSP-4.14 In order to inhibit memory in IMHV, the intracerebral injections have to be made after training, we found that injections before training into IMHV did not have any effect on memory.30 However, the injection of propranolol either subcutaneously before or into the LPO immediately after training affects |1-ARs (Gibbs and Summers, in prep). Propranolol30 and sotalol68 can be injected up to 25 minutes after training (Fig. 7). Inhibition of |2-ARs in the IMHV in

Figure 9. Dose response curves showing specificity ofAR subtype action. A. the dose response to CL316243 is shifted in a dose-dependent manner to prior administration of a non amnestic dose of the selective $3-AR antagonist SR59230 (A); but is not shifted by a non-amnestic dose of propranolol (B). Likewise, the dose response curve to zinterol is not shifted by a non amnestic dose of SR59230, but is shifted by a non amnestic dose ofpropranolol. (From ref. 27). Reprinted from Neuroscience, 95, 2000, pp. 913-922. Gibbs et al: Separate roles for $2- and ^-adrenoceptors in memory consolidation. Figure 3.

Figure 9. Dose response curves showing specificity ofAR subtype action. A. the dose response to CL316243 is shifted in a dose-dependent manner to prior administration of a non amnestic dose of the selective $3-AR antagonist SR59230 (A); but is not shifted by a non-amnestic dose of propranolol (B). Likewise, the dose response curve to zinterol is not shifted by a non amnestic dose of SR59230, but is shifted by a non amnestic dose ofpropranolol. (From ref. 27). Reprinted from Neuroscience, 95, 2000, pp. 913-922. Gibbs et al: Separate roles for $2- and ^-adrenoceptors in memory consolidation. Figure 3.

chicks given strongly reinforced training prevents consolidation and memory loss occurs after 30 minutes (Fig. 8A). This discrepancy in results between subcutaneous injection and injection into particular brain regions points out the importance of full investigations of the actions of drugs which may act at several receptor subtypes.

The selective P2-AR agonist, zinterol will enhance the consolidation of weakly reinforced learning when injected at 0 to 25 minutes after training and when given immediately after training, increases the duration of both short-term and intermediate memory.27 The specificity of action of zinterol was demonstrated by experiments in which we pre-administered (5 minutes after training with 20% anthranilate) non-amnestic doses of either propranolol or the selective P3-AR antagonist SR59230 (Table 3). The dose-response curve for zinterol was shifted to the right by propranolol but not by SR59230 (Fig. 9C and D).

$3-■Adrenoceptors

The action of the selective P3-AR agonist CL316243, shows specificity for the P3-AR in memory functioning. The dose response curve to CL316243 injected into the IMHV at 20 minutes after weakly reinforced learning shows dose dependent consolidation of memory. Prior administration of a non-amnestic dose of the selective P3-AR antagonist SR59230 shifts the dose response curve to the right in a dose dependent manner (Fig. 9A). Propranolol does not shift the dose response curve to CL316243 (Fig. 9B). Activation of both the ¡3- and the ¡2-AR are able to promote consolidation of memory. It appears that the action of low doses of noradrenaline and isoprenaline is on ¡3-ARs as the selective antagonist SR59230 inhibits the action of 0.1 nmol/hemisphere of noradrenaline and 0.03nmol/hemisphere of isoprenaline. This difference in the effective doses is in accord with the differences in affinity of the two catecholamines for the receptor. We hypothesize that endogenously released noradrenaline acts firstly on ¡3-ARs and then ¡2-ARs are recruited. The level of endogenous noradrenaline may be related to the level of reinforcement or in the case of aversive learning, to the level of stress invoked by the learning situation.

The selective P3-AR agonist CL316243 also enhances memory consolidation.27 Injection immediately after training results in a memory time course that appears to be the same as that seen with strongly reinforced training. Injection up to 20 minutes after weakly reinforced training is effective in promoting consolidation. The time window during which strongly reinforced learning can be inhibited by SR59230 is limited to injection 5 minutes after training (Fig. 7) and memory loss occurs after 10 minutes following training. The limited action of this antagonist was puzzling, but may be explained by the added complication of endogenous release of noradrenaline which will occur in many learning situations. In support of this interpretation, injection of SR59230 to chicks given weakly reinforced training was effective with injections at any time during the first part of intermediate memory (ITMA), i.e. from 10 to 25 minutes after training. To obtain this result, chicks had to be tested at 30 minutes after training. The endogenous noradrenaline, released with strongly reinforced training, may not act on ¡3-ARs when inhibited by the antagonist, but can still act on ¡2-ARs. In the weakly reinforced situation there should be less endogenous noradrenaline release.

We have been able to show enhancement of consolidation with two other P3-AR agonists— BRL37344 and CGP12177. However, BRL37344 appears to have two actions. At low doses (100pmol/hemisphere) it acts via P3-AR, whereas at higher doses (1 nmol / hemisphere) it acts on ¡2-ARs.28

Roles for Adrenoceptor Subtypes in the LPO

¡5 ¡-Adrenoceptors

As mentioned above, ¡1-ARs are involved in the LPO at the time of acquisition, during short-term memory, but do not appear to be involved in the IMHV at any of the times tested. The antagonist CGP20712 inhibits strongly reinforced training when injected into the LPO up to 2.5 minutes after training, and the selective agonist RO363 enhances memory when given up to 2.5 minutes after training (Gibbs and Summers, unpublished observation). Whether these agonists and antagonists act by enhancing consolidation or by some other action on short-term memory is not yet clear. It is possible that the ¡1-ARs are involved with the effects of arousal or attention in the basal ganglia at the time of acquisition and short-term memory.

a2-Adrenoceptors a2-ARs seem to be involved in memory consolidation in the LPO rather than in the IMHV. Pre-administration of the selective a2-AR antagonist yohimbine prevents enhancement of memory formation by noradrenaline when injected into the LPO (Fig. 6B), but has no effect on noradrenaline injected into the IMHV.30

Injection of the selective a2-AR agonist clonidine into the IMHV produces an effect, but at a higher dose and at more restricted times than when injected into LPO where injection is effective over the full time of labile memory. However, clonidine is lipophilic and crosses membranes readily, which makes it less than ideal for determination of sites of action. Experiments were therefore conducted with a hydrophilic a2-AR agonist, oxymetazoline which was found to have no effect on memory when injected into the IMHV, but is as effective as clonidine when given into the LPO. Likewise, yohimbine was not effective in the IMHV. Memory loss

Modeling Outcomes

Figure 10. A model of noradrenergic modulation of memory formation in the consolidation of memory in the chick. Noradrenergic input from the locus coeruleus activates |1-ARs in LPO (basal ganglia) at the time of or shortly after training. I3-AR activation in IMHV (association cortex) occurs before I2-AR activation in the IMHV, with the latter being dependent on a2-AR activation in LPO. It is likely that there could be other interactions between noradrenaline and adrenoceptors in other parts of the brain not yet explored.

Figure 10. A model of noradrenergic modulation of memory formation in the consolidation of memory in the chick. Noradrenergic input from the locus coeruleus activates |1-ARs in LPO (basal ganglia) at the time of or shortly after training. I3-AR activation in IMHV (association cortex) occurs before I2-AR activation in the IMHV, with the latter being dependent on a2-AR activation in LPO. It is likely that there could be other interactions between noradrenaline and adrenoceptors in other parts of the brain not yet explored.

after yohimbine occurs after 30 minutes (Fig. 8A). However, yohimbine is only effective in inhibiting consolidation when injected 10 or 15 minutes after training.

The danger of basing findings solely on drug administration by systemic injection is exemplified in our recent finding that yohimbine has a biphasic effect. Given subcutaneously 10 or 15 minutes after training, it inhibits memory consolidation, whereas given by the same route 2.5 or 25 minutes after training, it enhances consolidation. This does not occur following injections into either LPO or IMHV at these times. The may indicate an action of yohimbine in the locus coeruleus, and be related to the contradictory findings mentioned earlier.

Summary

By examining the response to administration of selective adrenoceptor subtype agonists and antagonists we have been able to map the time-course of noradrenaline involvement in memory acquisition and consolidation in chicks. By varying the route of administration, based on the response to subcutaneous injection, we have located different areas in the brain which, as well as being involved in memory,16 are involved in differential adrenoceptor activation at different times after training (Fig. 10).

Our research demonstrates the importance of systematic investigation to determine the time in the memory processing sequence when drugs are effective, the dose-response relationships for each drug and the site of action in the brain in order to conclude that a particular receptor is or is not involved in memory formation. Even when these factors are taken into account, the effects described are most likely still an oversimplification of the events in the brain that are influenced by noradrenaline in the acquisition and consolidation of a memory, since we have not touched on the possible involvement of noradrenaline in areas like the amygdala

(archistriatum), hippocampus and prefrontal cortex (caudal neostriatum) in the avian brain. But it does emphasize the caution needed when interpreting results from experiments using a single dose, a single route of injection and a single time of administration.

Input into different primary sensory brain regions and into various multimodal association areas will occur at the same time and cellular processing of the information will probably occur in more than one (if not many) of these areas. The potential is there for different influences or modulators employing many different neurotransmitter systems

As Lipp and Wolfer44 conclude - the reticular formation (and noradrenaline) has the potential to integrate and coordinate activity in many different brain regions during the acquisition and consolidation of memory. Other neurotransmitter and hormonal influences will also play a part in memory formation, some of which may involve noradrenaline (e.g., see ref. 58).

In the rodent, memory research is now focussing on hippocampus, amygdala, and the pre-frontal cortex, all of which are influenced by noradrenergic input. It is likely that these areas all have a different response to noradrenaline dependent on the subtype, and relative distribution of adrenoceptors. When information is available on the action of selective adrenoceptor agonists and antagonists administered to all these brain areas, a clearer picture of the interrelationships may emerge. The role of noradrenaline in modulating memory formation may be more complex than that of other neurotransmitters.

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